Clinical trials are likely to command greater international public attention. In recent years there has begun a steady stream of media and academic revelations about certain trials.
■ The failed Pennsylvanian Gene Therapy Trial in which a teenager (named Gelsinger) without his father’s knowledge or consent had been given a heavy dose of gene-altered viruses directly into his blood stream to treat his disease which had caused his liver to fail and his blood to thicken like jelly (OTC-ornithine transcarbamylase deficiency— a disease which leaves the liver unable to break down ammonia). There were also disturbing reports of some $37 million paid by Biogen Inc., to Genovo for the right to market these gene therapies (Nelson and Weiss 1999).
■ The striking off the medical register of a leading United Kingdom asthma researcher who was found guilty of serious professional misconduct and falsification of laboratory tests (Bulletin of Medical Ethics1999a).
■ Randomized trials of a well-known antidepressant which was suspected of a significant link to suicide by the users where there had been a failure in many cases and unsatisfactory reporting of the serious adverse events (Healy 1999).
■ The controversy over the use of placebos in trial to study drugs for rheumatoid arthritis where there was evidence of irreversible damage when the usual treatment was delayed for a period of months (The Lancet 1999).
■ Criticism that Research Ethics Committees, which approved the clinical trials, are not sufficiently resourced to adequately monitor trials (Chalmers 1996).
■ The controversy surrounding the placebo-controlled trials of short-course zidovudine to HIV-infected pregnant women to prevent perinatal HIV transmission. Long-term courses of zidovudine have been trialed in both the United States and France and proved to be effective. However, trials in Africa were conducted against a backdrop of a placebo arm where a best-proven therapeutic method had been established, and it was also unlikely that the country could ever afford the zidovudine treatment.
Clinical Trials in Australia: Some Background.Before examining the new clinical trial guidelines, some back-ground may be useful (AHEC 1992). Until 1983, sponsors of all clinical trials involving imported products were required to obtain Federal approval prior to the initiation of the trial. Pharmaceutical chemistry, preclinical, and clinical data were required in the same detail as that required to support applications to market a new chemical entity. In February 1983, review times were changed to 45 working days for early phase trials (Phase I and IIa) and 80 working days for later phase trials. In addition, a degree of deregulation was introduced in that sponsors were permitted to undertake additional trials without Federal review of the subsequent protocols, provided that the trial was within the approved dosage range and duration of treatment. Each trial required approval by the IEC of the host institution, and sponsors were required to notify the Federal agency at the time of approval by a HREC.
The TGA is a Commonwealth organization responsible for the registration of therapeutic goods including drugs and devices. The TGA conducts monitoring of licensed manufacturers who must comply with the Code of Good Manufacturing Practice; in addition, the TGA tests drugs and devices, reports and acts on problems, and ensures fair and truthful advertising (Therapeutic Goods Act).The scheduling of drugs is usually conducted under the various drug legislation of the States and Territories. In August 1987, revised procedures for review of clinical trials were introduced incorporating the concepts of a Clinical Trial Exemption (CTX) scheme under which the trial was permitted to proceed if no objection was raised by the TGA within a given time frame.
Under these arrangements, consideration of the essential safety aspects of a product proposed for use in a clini-cal trial remained a Federal responsibility, and consideration of the inter-related protocol was the responsibility of the HREC at the institution(s) at which the trial was to be conducted. The scientific validity of the study and the ability of the researcher and institution to effectively carry out the particular study were to be included in the HREC’s consideration of ethical aspects of the trial.
The CTN Scheme.In the early 1990s following the publication of the Baume Report the centralized system of approval for drug trials was replaced with a devolved approval system. HRECs were given the option of approving drug trials under the CTN. At first, there were considerable concerns about the implementation of this new scheme particularly in relation to potential legal liability (Day 1993). However, the implementation of the scheme has been realized through a process of self-selection under which only HRECs in large hospitals are now undertaking significant involvement in the CTN process. In the early 1990s it was recognized that there had been a major increase in the workload of those IECs that had undertaken this type of work (Chalmers 1996). In May 1991, links between clinical trials in Australia and marketing applications were severed. This allows clinical trials to be conducted while an application for registration for marketing is under review and vice versa.
The introduction of the CTN Scheme at the same time allows for drugs to be released for clinical trial purposes, provided authorities are notified of the trial beforehand and the trial is approved by the ethics com-mittee of the hospital or university where it is to be conducted. Only HRECs complying with the National Statement(National Statement1999), particularly Principles 2.1–2.48 on HRECs, are able to participate in these arrangements.
The main impact of the deregulation of clinical trials, from the point of view of HRECs, has been an expansion of their tasks and responsibilities to include the assessment of toxicological and safety data for trials submitted under the CTN Scheme. This was the subject of a specific review of the introduction of the CTN Scheme which was completed in 1993 (Day 1993). HRECs expressed particular concern over possible legal liability in administering these schemes and the need for appropriate indemnity. Of particular concern was the fact that some HRECs did not have the expertise to assess pharmacology or toxicology data. The responsibility of HRECs was reflected in the Therapeutic Goods Regulations as amended by the Therapeutic Goods Act. This provides that the institution which is responsible for conducting the trial must take advice from the IEC (now HREC) on the conduct of the trial, give approval to the trial (the institution may be responsible for more than one site), set terms of approval for the trial which are no less restrictive that the ethics committee’s advice, and withdraw approval for the trial if the ethics committee advises that continuation of the trial is not appropriate.
The move to using the CTN Scheme has been steadily increasing. By mid-1999, the TGA reported that some 1,500 were proceeding under CTN and only 10 under the CTX (information provided by Manager of TGA to AHEC, July 1999). In essence the CTN is a deregulated system where all responsibility for the trial rests with the institution, and notification only is given to the TGA about the conduct of the trial. On the other hand, under the CTX Scheme the TGA remains responsible for the safety aspects of the product and charges fees for this service.
The National Statement Principles.The new Australian National Statement(National Statement1999) is a comprehensive and uniform set of guidelines which includes general principles and sections (Principles) on many aspects of research (e.g., epidemiological research, genetic research, use of human tissue, psychological research, and multicenter research). The National Statementincludes more detailed guidelines of the establish-ment, composition, operation, functions, and duties of HRECs.
The National Statementincludes a section dealing with clinical trials, which are defined to apply to natural therapies and other interventions. The previous Statement on Human Experimentationincluded a supplementary note on clinical trials but in considerably less detail than the National Statement. The introduction to Principles
A clinical trial is a study involving humans to find out whether an intervention, including treatments or diagnostic procedures, which it is believed may improve a person’s health, actually does so. A clinical trial can involve testing a drug, a surgical or other therapeutic or preventive procedure, or a therapeutic, preventive or diagnostic device or service. Any intervention, including so-called ‘natural’ therapies and other forms of complementary medicine,can be tested in this way. Other related disciplines also conduct research, which involves similar ethical considerations to those raised in clinical trials.
In pharmaceutical and medical device trials there are established codes of good clinical research practice which define clearly what is meant by a clinical trial for those purposes.
12. Clinical Trials has principal application in the context of biomedical clinical trials but should also apply to any other intervention claiming therapeutic benefit, wherever provided or conducted (emphasis added).
The trial must be properly designed and conducted and be approved by a HREC. The HREC that considers the clinical trial is not required to judge the actual science involved. Rather the HREC must ensure that it is
“…sufficiently informed on all aspects of a research protocol, including its scientific and statistical validity”
(National Statement1999, Principle 2.8). Principle 12.1 goes on to state:
The aims of every trial must be precisely stated in a protocol presented to and approved by a Human Research Ethics Committee (HREC) and every trial must be conducted by researchers with suitable experience, qualifications and competence and, where applicable, adequate training in relevant procedures including the use of any device being trialed.
See also Principle 12.2, which gives details on scientific hypothesis and methodology.
A HREC, before granting approval to a clinical trial, must be satisfied that the protocol conforms to a num-ber of international obligations in addition to the National Statementas well as relevant Australian laws. The Code of Good Manufacturing Practice issued by the TGA is broadly similar to many equivalent documents in other countries (TGA 1991). In addition, it is recognized that Australian researchers may be involved in multi-center international trials. Indeed, in the case of American trials, Australian researchers are required to comply with American regulations promulgated by the FDA. There was a quite deliberate intention in the revision of the National Statementto ensure consistency with established international guidelines. In this regard, Principle 12.3 of the National Statementprovides:
An HREC, before granting approval to a clinical trial, must be satisfied that the protocol conforms to:
(a) this Statement;
(b) the World Medical Association Declaration of Helsinki;
(c) where relevant, the CPMP/ICH Note for Guidance on Good Clinical Practice(CPMP/ICH-135/95) and the ISO 14155 Clinical Investigation of Medical Devicesand the requirements of the TGA;
(d) any requirements of relevant Commonwealth or State/Territory laws.
Principles 12.12 and 12.13 also refer to relevant standards.
The National Statementalso includes a specific guideline on the acceptable uses of placebos in clinical trials and, essentially, outlaws their use where there is an effective treatment available (National Statement1999, Principle 12.4). There was considerable discussion in relation to this particular guideline. In the end the AHEC, in publishing the guideline, preferred the view that it is difficult to create a research project (testing a
hypothesis when there is a treatment available which has been clearly shown to be effective). To ignore a proven effective treatment breaches the medical practitioner’s duty to provide best available treatment to the patient.
12.4 The use of a placebo alone or the incorporation of a non-treatment control group is ethically unacceptable in a controlled trial where:
(a) other available treatment has already been clearly shown to be effective;(emphasis added) and (b) there is risk of significant harm in the absence of treatment.
If there is genuine uncertainty about the net clinical benefit of treatment, a placebo controlled trial or a trial with a no-treatment arm may be considered.
Apart from general guidelines against conflict of interest, (National Statement1999, Principles 1.1 and 2.20) researchers are required to declare financial or business interests in relation to the clinical trial presented for approval before the HREC (National Statement: 1999, Principles 12.5 and 12.6). A researcher is not required to disclose every interest to research participants; rather, a HREC is required to examine the budget of the clinical trial and consider aspects of the budget that raise ethical issues. The HREC then decides whether any informa-tion in relainforma-tion to the financial aspects of the trials should be declared to participants.
12.5 A researcher must inform an HREC of any business or other similar association which may exist between a researcher and the supplier of a drug or surgical or other device to be used in the trial.
12.6 An HREC must examine those aspects of the budgets of clinical trials which raise ethical issues, including capitation fees, payments to researchers, institutions or organisations involved in the research, current and consequential institutional or organisational costs and costs which may be incurred by participants. It should be satisfied that:
(a) payment in money or kind would not cause researchers to apply pressure to individuals so as to obtain their consent to participate;
(b) payment in money or kind could not influence the findings of the research;
(c) there will be disclosure to the research participants of relevant aspects of those budgets;
and
(d) funding is sufficient to conduct and complete the trial so that participants are not disadvantaged by premature cessation.
Since the early 1990s the NHMRC has published guidelines requiring HRECs to review the compensation arrangements for the trial (NHMRC 1994). Principle 12.7 of the National Statementprovides that compensation arrangements must be in place for participants who may be injured in the trial.
12.7 An HREC must be satisfied, before approving a clinical trial, that arrangements exist to ensure adequate compensation to participants for any injury suffered as a result of participation in the trial.
There are, finally, guidelines about the reporting of all serious or unexpected adverse events, review of the trial, suppression of the trial, and privacy of findings (National Statement1999, Principles 12.8–12.11).
The new Principleshave deliberately aimed to put greater responsibility on the HREC that approves a trial, the reality being that the preponderance of Australian clinical trials of drugs and devices are performed under
the terms of the CTN Scheme. In summary, the HREC must be satisfied that the trial is properly designed (including methods of recruitment and statistical significance). The HREC must also decide whether the trial conforms with the international standards where relevant (CPMP/ICH 1995). Placebos should not be used where they are already proven effective available treatment. In addition, conflicts of interest must be declared, funding arrangements reviewed; compensation arrangements put in place; all serious or unexpected adverse events reported by the researcher; the trial monitored and reviewed; and information on the trials kept in a durable form to protect privacy. The monitoring of trials and research generally has been a continuing difficulty in Australia (Chalmers 1996).
Again, the new Principlesare only a start and further questions remain for consideration for the further development for ethical clinical trials. For example, should the same rules apply where the trial involves an entirely new procedure, e.g., malaria vaccine, where new knowledge is being developed and the risks attaching to long-term effects are quite unknown or unpredictable at this early stage? Should there be different rules for autologous immuno-therapies and certain types of oncological gene therapies where the patients are usually suffering from terminal illnesses? Should there be a separation of drug trials conducted in the public institutions as opposed to those conducted in private institutions? Should special rules apply to trials conducted by the doctors in general practice whose primary duties to the patient may conflict with any research protocol in which the doctor is involved? Should different rules apply where the trial involves blood or tissues on which genetic information is to be gathered? This is not a comprehensive list but illustrative only (Mant 1999)